The classification of COPD based simply on magnitude of forced expiratory flow abnormality, is[unreadable] inadequate and of limited value in individualizing therapeutic interventions to influence the natural history of[unreadable] the disease. Our global hypothesis is that "COPD is a heterogeneous group of definable anatomic and[unreadable] physiologic disease processes, each with its own molecular and cellular processes that determine[unreadable] disease manifestation and progression." We propose to use 2 well established cohorts of current and[unreadable] former smokers to efficiently recruit and execute a cross sectional study of 800 subjects with a wide range of[unreadable] disease manifestation and then to follow 450 of them longitudinally over a 2-3 year course.[unreadable] (SA1): To use quantitative CT (QCT) determinants of airway remodeling and emphysema and their[unreadable] associations with other physiologic and functional indices of COPD to define unique clinicopathologic[unreadable] disease subclasses or phenotypes, and (SA2) To Associate Peripheral Blood Molecular[unreadable] and Cellular Biomarkers with Unique Clinical and Lung Histopathologic Phenotypes. We believe,[unreadable] based upon preliminary data, that ascertainable variation in immune cell function, cytokine expression, and[unreadable] genetic factors are different between and can be used to distinguish unique pathophysiologic subsets of[unreadable] patients. We aim nothing short of providing justification for reclassification of COPD into more biologically[unreadable] relevant categories that could direct development of more effective patient specific therapies.[unreadable] In our (SA3) we further explore the recent observations from the laboratory of our co-investigator, Dr. J[unreadable] Hogg, of a dramatic association between peripheral airway luminal mucous content LC% and poor survival.[unreadable] Findings of surrogate markers associated with this process could have immense importance because, to[unreadable] date, we have been unable to identify an association between the severity of LC% and any clinical or[unreadable] physiologic feature. We hypothesize that: Molecular and cellular biomarkers and QCT variables of[unreadable] COPD, in a subgroup of severe patients characterized prior to lung transplantation, are associated[unreadable] with severity of luminal content (LC) occlusion of peripheral airways measured in lung tissue using[unreadable] standard morphometric techniques. Identification of non-invasive surrogates for this condition, could[unreadable] have major implications in determining prognosis or targeting individual therapy.